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Volume 27
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Review

Mechanistic Links Underlying the Comorbidity of Osteoporosis and Osteoarthritis: Cell Fate Plasticity Driven by the Subchondral Bone Microenvironment

by
Jian Zhang
1,†,
Bingbing Chen
2,†,
Qianqian Yang
1,
Heguo Yan
1,
Niqin Xiao
1,
Yundong Xu
1,
Sanjin Zeng
2,
Shengyi Zhao
2,
Rong Wang
2,
He Qian
2,
Zhaohu Xie
2,
Jing Xie
2,* and
Zhaofu Li
1,*
1
The First Clinical Medical College, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China
2
College of Basic Medical Sciences, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to the work.
Int. J. Mol. Sci. 2026, 27(13), 5757; https://doi.org/10.3390/ijms27135757 (registering DOI)
Submission received: 19 May 2026 / Revised: 15 June 2026 / Accepted: 24 June 2026 / Published: 25 June 2026
(This article belongs to the Special Issue Advanced Molecular Mechanism of Pathogenesis of Osteoarthritis)
Review Reports Versions Notes

Abstract

Osteoporosis (OP) and osteoarthritis (OA) are two common degenerative musculoskeletal disorders associated with aging and are traditionally classified and managed as distinct disease entities. Emerging evidence suggests that OP and OA may share bidirectional associations and common biological mechanisms, and that under specific pathological conditions they may develop into a mutually reinforcing comorbid state. The comorbidity of osteoporosis and osteoarthritis (OP–OA) is not a simple superimposition of bone loss and cartilage degeneration; rather, it represents a disorder of the osteochondral unit centered on disruption of the subchondral bone microenvironment. Alterations in the structural strength, remodeling dynamics, vascular and neural status, and bone marrow lesions of subchondral bone collectively reshape the local microenvironment, thereby directly affecting mechanical signal transmission and cellular behavior within the joint. Focusing on the subchondral bone microenvironment as the central pathological nexus, this review systematically summarizes how mechanical imbalance, aberrant bone remodeling, inflammatory activation, metabolic dysregulation, and cellular senescence jointly remodel the local niche in OP–OA comorbidity. These microenvironmental changes further induce phenotypic remodeling and fate deviation of bone marrow mesenchymal stem cells, bone remodeling-related cells, osteoimmune cells, and chondrocytes. On this basis, we integrate the regulatory roles of developmental signaling, mechanotransduction pathways, and inflammatory–immune signaling networks, and propose that microenvironment-driven cell fate plasticity may serve as a key mechanistic hub promoting the initiation and progression of OP–OA comorbidity as well as the persistent destabilization of the osteochondral unit. This perspective may help overcome the limitations of current studies that address OP and OA separately, and may provide a theoretical framework for early identification and stratification, biomarker discovery, and combined precision-targeted interventions for this comorbid condition.
Keywords: osteoporosis; osteoarthritis; comorbidity; osteochondral unit; subchondral bone; microenvironment; cell fate plasticity osteoporosis; osteoarthritis; comorbidity; osteochondral unit; subchondral bone; microenvironment; cell fate plasticity

Share and Cite

MDPI and ACS Style

Zhang, J.; Chen, B.; Yang, Q.; Yan, H.; Xiao, N.; Xu, Y.; Zeng, S.; Zhao, S.; Wang, R.; Qian, H.; et al. Mechanistic Links Underlying the Comorbidity of Osteoporosis and Osteoarthritis: Cell Fate Plasticity Driven by the Subchondral Bone Microenvironment. Int. J. Mol. Sci. 2026, 27, 5757. https://doi.org/10.3390/ijms27135757

AMA Style

Zhang J, Chen B, Yang Q, Yan H, Xiao N, Xu Y, Zeng S, Zhao S, Wang R, Qian H, et al. Mechanistic Links Underlying the Comorbidity of Osteoporosis and Osteoarthritis: Cell Fate Plasticity Driven by the Subchondral Bone Microenvironment. International Journal of Molecular Sciences. 2026; 27(13):5757. https://doi.org/10.3390/ijms27135757

Chicago/Turabian Style

Zhang, Jian, Bingbing Chen, Qianqian Yang, Heguo Yan, Niqin Xiao, Yundong Xu, Sanjin Zeng, Shengyi Zhao, Rong Wang, He Qian, and et al. 2026. "Mechanistic Links Underlying the Comorbidity of Osteoporosis and Osteoarthritis: Cell Fate Plasticity Driven by the Subchondral Bone Microenvironment" International Journal of Molecular Sciences 27, no. 13: 5757. https://doi.org/10.3390/ijms27135757

APA Style

Zhang, J., Chen, B., Yang, Q., Yan, H., Xiao, N., Xu, Y., Zeng, S., Zhao, S., Wang, R., Qian, H., Xie, Z., Xie, J., & Li, Z. (2026). Mechanistic Links Underlying the Comorbidity of Osteoporosis and Osteoarthritis: Cell Fate Plasticity Driven by the Subchondral Bone Microenvironment. International Journal of Molecular Sciences, 27(13), 5757. https://doi.org/10.3390/ijms27135757

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